Microtubules are polymers that serve critical roles in establishing and maintaining cellular architecture. Microtubules are the target of important anticancer drugs such as the vinca alkaloids and taxol (paclitaxel), and are thought to play a role in neurodegenerative diseases such as Alzheimer's. Microtubules are dynamic polymers of the protein tubulin, a GTPase, and the energy of GTP hydrolysis drives dynamic instability whereby microtubules spontaneously switch between periods of polymerization and rapid depolymerization. This behavior is regulated by cells to achieve rapid restructuring of the cytoskeleton. To better understand dynamic instability we have developed methods to track microtubule polymerization with nanometer scale resolution, thereby revealing fundamental behaviors that were not resolved by traditional approaches. This work has led to a fundamental reassessment of the molecular mechanics underlying dynamic instability, and provides important insight into the mechanisms by which drugs and microtubule associated proteins can regulate microtubule dynamics. Here we combine nanometer resolution studies of microtubule dynamics with molecular modeling to understand the detailed actions of taxol at clinically relevant doses, and the microtubule regulating protein tau, which plays an important role in Alzheimer's and other neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: The results of proposed studies will yield a better understanding of the mechanics of microtubule assembly, and how these are altered by effective chemotherapy drugs, and the tau protein, which plays a central role in Alzheimer's and other neurodegenerative diseases. In addition to providing a better understanding of processes important for understanding and treating cancer and neurodegenerative disease, broad impact across the biomedical sciences will be achieved by advancing transformative technology for studying biological mechanics with nanometer scale precision.